1. Field of the Invention
The invention relates to polycyclic nucleotide xanthine phosphodiesterase V inhibitors.
2. Description of Related Art
Phosphodiesterase (xe2x80x9cPDExe2x80x9d) V inhibitor compounds are described by Kenneth J. Murray in Phosphodiesterase VA Inhibitors, DN and P 6(3), pp. 150-156 (April, 1993), which is hereby incorporated herein by reference in its entirety, to have potential therapeutic value for a number of physiological disorders. One compound disclosed in the Murray article is MIMAX, a polycyclic xanthine PDE V inhibitor substituted at its 8-position with a xe2x80x94NHCH3 group.
U.S. Pat. No. 5,409,934, which is hereby incorporated herein by reference in its entirety, discloses a series of xanthine PDE V inhibitors that are substituted at the 8-position with, among other possibilities, one of the following groups: xe2x80x94NO2, xe2x80x94NRsRt or xe2x80x94NR6SO2R5, where Rs and Rt, independently of one another, are each a hydrogen atom or an alkyl group, or Rs and Rt, together with the nitrogen atom to which they are both attached, form a phthalimido group, R5 is an alkyl or aryl group, and R6 is a hydrogen atom or xe2x80x94SO2R7, where R7 is an alkyl or aryl group.
U.S. Pat. No. 5,470,579, which is hereby incorporated herein by reference in its entirety, discloses a xanthine PDE V inhibitor having a substituted or unsubstituted xe2x80x94NH2 group at the 8-position, for example, xe2x80x94NHR, where R is a C1-C6 alkyl group.
WO 93/23401, which is hereby incorporated herein by reference in its entirety, discloses xanthine PDE V inhibitors that are substituted at the 8-position with xe2x80x94NH(CH2)2CH(CH2OR4)2.
WO 92/05176, which is hereby incorporated herein by reference in its entirety, discloses 8-acylaminoxanthine PDE V inhibitors that are substituted at the 8-position with xe2x80x94NHCOC6H5COOH.
WO 92/05175, which is hereby incorporated herein by reference in its entirety, discloses 8-aminoxanthine PDE V inhibitors that are substituted at the 8-position with xe2x80x94NH2 or xe2x80x94NHR, where R is an alkyl, arylalkyl or unsaturated heterocyclic (e.g., heteroaryl) group.
Specific PDE V inhibitors have been found useful for specific indications. For example, the use of PDE V inhibitors for treating impotence has met with commercial success with the introduction of sildenafil citrate, better known as Viagra(copyright) (Pfizer, N.Y., N.Y.). The chemistry and use of Viagra(copyright), including its mechanism of action in treating erectile dysfunction, are taught in EP 0 702 555 B1, which is hereby incorporated herein by reference in its entirety. Additional PDE V inhibitors useful for treating erectile dysfunction are disclosed in WO 99/24433, which is hereby incorporated herein by reference in its entirety.
Erectile dysfunction is a treatable and highly recognized health concern, affecting more than 30 million men in the United States, including one in four over age 65. Erectile dysfunction occurs when a man consistently is unable to sustain an erection sufficient for conducting sexual intercourse. In the past, psychological reasons were the most common explanation for erectile dysfunction or it was considered a natural part of aging. However, researchers today acknowledge that more than 70 percent of instances of erectile dysfunction are due to physical or medical problems. There are several factors that may contribute to erectile dysfunction, including:
Poor blood circulationxe2x80x94atherosclerosis or hardening of the arteries, high blood pressure and high cholesterol.
Neurological disordersxe2x80x94multiple sclerosis, Alzheimer""s disease and Parkinson""s disease.
Hormone imbalancesxe2x80x94diabetes, thyroid disorders and low testosterone levels.
Traumaxe2x80x94spinal cord injury, prostate surgery or other trauma to the pelvic area.
Prescription and over-the-counter medicationsxe2x80x94blood pressure medications, antidepressants and certain drug combinations.
Lifestyle habitsxe2x80x94smoking, alcohol abuse and using illegal drugs.
U.S. Pat. No. 5,939,419 and U.S. Pat. No. 5,393,755, both of which are hereby incorporated herein by reference in their entirety, disclose polycyclic guanine PDE V derivatives that are useful for the treatment of cardiovascular and pulmonary disorders.
As has been shown by the representative art cited above, certain xanthine/guanine PDE V inhibitors have been found to be useful for treating cardiovascular and pulmonary disorders, while some others have been found useful for treating impotence. It has been further shown that certain xanthine PDE V inhibitors can be substituted at the 8-position by a variety of groups, including nitro and unsubstituted or substituted amino groups. The substituted amino groups include saturated heterocycles, where the nitrogen atom and its substituents together form an unsaturated heterocyclic group (e.g., xe2x80x94NRxRy can form a heterocycle).
It is an object of this invention to provide a polycyclic xanthine PDE V inhibitor that possesses beneficial therapeutic properties.
It is a further object of the invention to provide a polycyclic xanthine PDE V inhibitor that has especially useful pharmacological properties.
It is yet another object of the invention to provide a polycyclic xanthine PDE V inhibitor that has good metabolic stability.
It is still another object of the invention to provide a polycyclic xanthine PDE V inhibitor that is effective for treating a variety of physiological symptoms and diseases in which PDE V plays a role.
It is also an object of the invention to provide a polycyclic xanthine PDE V inhibitor that is especially effective for treating erectile dysfunction with minimal side effects.
These and other objects of the invention will become apparent as the description progresses.
Definitions and Usage of Terms
The following definitions and terms are used herein or are otherwise known to a skilled artisan. Except where stated otherwise, the following definitions apply throughout the specification and claims. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Hence, the definition of xe2x80x9calkylxe2x80x9d applies to xe2x80x9calkylxe2x80x9d as well as the xe2x80x9calkylxe2x80x9d portions of xe2x80x9chydroxyalkyl,xe2x80x9d xe2x80x9chaloalkyl,xe2x80x9d xe2x80x9calkoxy,xe2x80x9d etc.
The term xe2x80x9cchemically-compatible,xe2x80x9d as used herein, means that a substituent or variable in a structure, process or the like is selected to be capable of resulting in a stable compound.
The term xe2x80x9csubstitutedxe2x80x9d or the phrase xe2x80x9cwith . . . one or more substituents,xe2x80x9d as used herein, means the replacement of one or more atoms or radicals, usually hydrogen atoms, in a given structure with a chemically-compatible atom(s) or radical(s) selected from a specified group. In the situations where more than one atom or radical may be replaced with substituents selected from the same specified group, the substituents may be, unless otherwise specified, either the same or different at every position. Radicals of specified groups, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, arylalkyl, alkylaryl, heterocycloalkyl, aryl and heteroaryl groups, independently of or together with one another, may be substituents for any substituted group, unless otherwise known, stated or shown to be to the contrary.
Representative substituents for alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, arylalkyl, alkylaryl, aryl, heteroaryl and heterocycloalkyl groups include, but are not limited to, the following moieties: alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, arylalkyl, alkylaryl, aryl, heteroaryl, heterocycloalkyl, hydroxyalkyl, arylalkyl, aminoalkyl, haloalkyl, thioalkyl, alkylthioalkyl, carboxyalkyl, imidazolylalkyl, indolylalkyl, mono-, di- and trihaloalkyl, mono-, di- and trihaloalkoxy, amino, alkylamino, dialkylamino, alkoxy, hydroxy, halo (e.g., xe2x80x94Cl and xe2x80x94Br), nitro, oximino, xe2x80x94COOR50, xe2x80x94COR50, xe2x80x94SO0-2R50, xe2x80x94SO2NR50R51, NR52SO2R50, xe2x95x90C(R50R51), xe2x95x90Nxe2x80x94OR50, xe2x95x90Nxe2x80x94CN, xe2x95x90C(halo)2, xe2x95x90S, xe2x95x90O, xe2x80x94CON(R50R|), xe2x80x94OCOR50, xe2x80x94OCON(R50R51), xe2x80x94N(R52)CO(R50), xe2x80x94N(R52)COOR50 and xe2x80x94N(R52)CON(R50R51), where:
R50, R51 and R52 may be independently selected from the following: a hydrogen atom and a branched or straight-chain, C1-6 alkyl, C3-6 cycloalkyl, C4-6 heterocycloalkyl, heteroaryl and aryl group, with or without substituents. When permissible, R50 and R51 can be joined together to form a carbocyclic or heterocyclic ring system. R50, R51 and R52 may also include: 
where,
R40 and R41 are, independently of one another, each a hydrogen atom or a branched or straight-chain, optionally substituted, alkyl, cycloalkyl, heterocycloalkyl, halo, aryl, imidazolylalkyl, indolylalkyl, heteroaryl, arylalkyl, arylalkoxy, heteroarylalkyl, heteroarylalkoxy, aminoalkyl, haloalkyl, mono-, di- or trihaloalkyl, mono-, di- or trihaloalkoxy, nitro, cyano, alkoxy, hydroxy, amino, phosphino, phosphate, alkylamino, dialkylamino, formyl, alkylthio, trialkylsilyl, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, morpholino, thioalkyl, alkylthioalkyl, carboxyalkyl, oximino, xe2x80x94COOR50, xe2x80x94COR50, xe2x80x94SO0-2R50, xe2x80x94SO2NR50R51, xe2x80x94NR52SO2R50, xe2x80x94CON(R50R51), xe2x80x94OCON(R50R51), xe2x80x94N(R52)CO(R50), xe2x80x94N(R52)COOR50, xe2x80x94N(R52)CON(R50R51) or xe2x80x94OCONR50 group, where, R50, R51 and R52 are as defined above;
R42 is a hydrogen atom or a branched or straight-chain, optionally substituted, alkyl, alkenyl, arylalkyl or acyl group; and
R43 is a hydrogen atom or a branched or straight-chain, optionally substituted, alkyl or aryl group;
wherein, the optional substituents are defined the same as above for the one or more substituents.
Preferred substituents on aryl and heteroaryl groups include, but are not limited to, any of the moieties recited above in the definition for R40 and R41.
The term xe2x80x9cheteroatom,xe2x80x9d as used herein, means a nitrogen, sulfur, or oxygen atom. Multiple heteroatoms in the same group may be the same or different.
The term xe2x80x9chydrocarbon,xe2x80x9d as used herein, means a compound or radical consisting of only carbon and hydrogen atoms, including aliphatic, aromatic, normal, saturated and unsaturated hydrocarbons.
The term xe2x80x9calkyl,xe2x80x9d as used herein, means an unsubstituted or substituted, straight or branched, hydrocarbon chain (i.e., comprising carbon and hydrogen atoms bonded together), having, preferably, from one to twenty-four carbon atoms, more preferably, from one to twelve carbon atoms, and most preferably, from one to eight carbon atoms.
The term xe2x80x9ccycloalkylxe2x80x9d or xe2x80x9ccycloalkane,xe2x80x9d as used herein, means an unsubstituted or substituted, saturated, stable non-aromatic carbocyclic ring, having, preferably, from three to fifteen carbon atoms, more preferably, from three to eight carbon atoms. The carbon ring radical is saturated and may be fused, for example, benzofused, with one to three cycloalkyl, aromatic, heterocyclic or heteroaromatic rings. The cycloalkyl may be attached at any endocyclic carbon atom that results in a stable structure. Preferred carbocycles have from five to six carbons. Examples of carbocycle radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
The term xe2x80x9calkenyl,xe2x80x9d as used herein, means an unsubstituted or substituted, unsaturated, straight or branched, hydrocarbon chain having at least one double bond present and, preferably, from two to fifteen carbon atoms, more preferably, from two to twelve carbon atoms.
The term xe2x80x9ccycloalkenyl,xe2x80x9d as used herein, means an unsubstituted or substituted, unsaturated carbocyclic ring having at least one double bond present and, preferably, from three to fifteen carbon atoms, more preferably, from five to eight carbon atoms. A cycloalkenyl goup is an unsaturated carbocyclic group. Examples of cycloalkenyl groups include cyclopentenyl and cyclohexenyl.
The term xe2x80x9calkynyl,xe2x80x9d as used herein, means an unsubstituted or substituted, unsaturated, straight or branched, hydrocarbon chain having at least one triple bond present and, preferably, from two to twelve carbon atoms, more preferably, two to ten carbon atoms.
The term xe2x80x9cbicycloalkyl,xe2x80x9d as used herein, represents a saturated linearly fused or bridged carbocyclic ring having, preferably, from 5 to 12 carbon atoms.
The term xe2x80x9caryl,xe2x80x9d as used herein, means a substituted or unsubstituted, aromatic, mono- or bicyclic carbocyclic ring system having from one to two aromatic rings. The aryl moiety will generally have from 6 to 14 carbon atoms with all available substitutable carbon atoms of the aryl moiety being intended as possible points of attachment. Representative examples include phenyl, tolyl, xylyl, cumenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. If desired, the carbocyclic moiety can be substituted with from one to five, preferably, one to three moieties, such as mono-through pentahalo, alkyl, trifluoromethyl, phenyl, hydroxy, alkoxy, phenoxy, amino, monoalkylamino, dialkylamino and the like.
The term xe2x80x9cheteroaryl,xe2x80x9d as used herein, means a mono- or bicyclic ring system containing one or two aromatic rings and at least one nitrogen, oxygen or sulfur atom in an aromatic ring. Heteroaryl groups (including bicyclic heteroaryl groups) can be unsubstituted or substituted with a plurality of substituents, preferably, one to five substituents, more preferably, one, two or three substituents (e.g., mono-through pentahalo, alkyl, trifluoromethyl, phenyl, hydroxy, alkoxy, phenoxy, amino, monoalkylamino, dialkylamino and the like). Typically, a heteroaryl group represents a cyclic group of five or six atoms, or a bicyclic group of nine or ten atoms, at least one of which is carbon, and having at least one oxygen, sulfur or nitrogen atom interrupting a carbocyclic ring having a sufficient number of pi (xcfx80) electrons to provide aromatic character. Representative heteroaryl (heteroaromatic) groups are pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, benzofuranyl, thienyl, benzothienyl, thiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, isothiazolyl, benzothiazolyl, benzoxazolyl, oxazolyl, pyrrolyl, isoxazolyl, 1,3,5-triazinyl and indolyl groups.
The term xe2x80x9carylalkyl,xe2x80x9d as used herein, means an alkyl moiety substituted with an optionally substituted, aryl or heteroaryl group. Representative arylalkyl groups include a benzyl group and fused bicyclic systems which contain one aryl group.
The term xe2x80x9calkylaryl,xe2x80x9d as used herein, means an aryl or heteroaryl moiety substituted with an optionally substituted, alkyl group. Representative alkylaryl groups include o-, m- and p-linked tolyl and xylyl groups.
Unless otherwise known, stated or shown to be to the contrary, the point of attachment for a multiple term substituent (multiple terms that are combined to identify a single moiety) to a subject structure is through the last named term of the multiple term. For example, an xe2x80x9carylalkylxe2x80x9d substituent attaches to a targeted structure through the xe2x80x9calkylxe2x80x9d portion of the substituent. Conversely, when the substituent is xe2x80x9calkylarylxe2x80x9d, it attaches to a targeted structure through the xe2x80x9carylxe2x80x9d portion of the substituent. Similarly, a cycloalkylalkyl substituent attaches to a targeted through the latter xe2x80x9calkylxe2x80x9d portion of the substituent (e.g., Structure-alkyl-cycloalkyl).
The term xe2x80x9cheterocycloalkyl,xe2x80x9d as used herein, means an unsubstituted or substituted, saturated cyclic ring system having from three to fifteen members, preferably, from three to eight members, and comprising carbon atoms and at least one heteroatom as part of the ring.
The term xe2x80x9cheterocyclic ringxe2x80x9d or xe2x80x9cheterocycle,xe2x80x9d as used herein, means an unsubstituted or substituted, saturated, unsaturated or aromatic ring, comprised of carbon atoms and one or more heteroatoms in the ring. Heterocyclic rings may be monocyclic or polycyclic. Monocyclic rings preferably contain from three to eight atoms, most preferably, five to seven atoms. Polycyclic ring systems consisting of two rings preferably contain from six to sixteen atoms, most preferably, ten to twelve atoms. Polycyclic ring systems consisting of three rings contain, preferably, from thirteen to seventeen atoms, most preferably, fourteen to fifteen atoms. Each heterocyclic ring has at least one hetero atom. Unless otherwise stated, the heteroatoms may be independently selected from the following: nitrogen, sulfur and oxygen atoms.
The term xe2x80x9ccarbocyclic ringxe2x80x9d or xe2x80x9ccarbocycle,xe2x80x9d as used herein, means an unsubstituted or substituted, saturated, unsaturated or aromatic (e.g., aryl), hydrocarbon ring, unless otherwise specifically identified. Carbocycles may be monocyclic or polycyclic. Monocyclic rings preferably contain from three to eight atoms, most preferably, five to seven atoms. Polycyclic rings having two rings preferably contain from six to sixteen atoms, most preferably, ten to twelve atoms, and those having three rings preferably contain from thirteen to seventeen atoms, most preferably, fourteen to fifteen atoms.
The term xe2x80x9calkoxy,xe2x80x9d as used herein, means an oxygen atom bonded to a hydrocarbon chain, such as an alkyl or alkenyl group (e.g., xe2x80x94O-alkyl or xe2x80x94O-alkenyl). Representative alkoxy groups include methoxy, ethoxy, a isopropoxy groups.
The term xe2x80x9chydroxyalkyl,xe2x80x9d as used herein, means a substituted hydrocarbon chain, preferably, an alkyl group, having at least one hydroxy substituent (ie., xe2x80x94OH). Additional substituents to the alkyl group may also be present. Representative hydroxyalkyl groups include hydroxymethyl, hydroxyethyl and hydroxypropyl groups.
The term xe2x80x9ccarboxyalkyl,xe2x80x9d as used herein, means a substituted hydrocarbon chain, preferably, a substituted alkyl group, which has a carboxyl substituent (e.g., xe2x80x94COOH) and may also have additional substituents (such as one of the representative substituents identified above for the term xe2x80x9csubstitutedxe2x80x9d). Representative carboxyalkyl groups include carboxymethyl (xe2x80x94CH2CO2H) and carboxyethyl (xe2x80x94CH2CH2CO2H) groups, and derivatives thereof, such as the corresponding esters.
The term xe2x80x9caminoalkyl,xe2x80x9d as used herein, means an alkyl group substituted with an amine moiety (e.g., xe2x80x94alkylNH2), such as aminomethyl.
The term xe2x80x9calkylamino,xe2x80x9d as used herein, means an amino moiety having from one or two alkyl substituents (e.g., xe2x80x94NH-alkyl), such as dimethylamino.
The term xe2x80x9calkenylamino,xe2x80x9d as used herein, means an amino moiety having from one or two alkenyl substituents, where the nitrogen atom of the amino group is not attached to the alkene-forming carbon atom (e.g., xe2x80x94NHxe2x80x94CH2-alkenyl), such as dibutenylamino.
The term xe2x80x9carylamino,xe2x80x9d as used herein, means an amine moiety substituted with an aryl group (i.e., xe2x80x94NH-aryl).
The term xe2x80x9calkylimino,xe2x80x9d as used herein, means an imino moiety having one alkenyl or two alkyl substituents (e.g., xe2x80x94Cxe2x95x90N-alkyl).
The term xe2x80x9coximino,xe2x80x9d as used herein, means compounds containing the xe2x80x94Cxe2x95x90Nxe2x80x94OR69 radical, where R69 is a hydrogen atom or an alkyl or aryl group.
The term xe2x80x9caroyl,xe2x80x9d as used herein, means the radical Rxe2x80x94COxe2x80x94; where R is an aromatic group. Representative aroyls are benzoyl and naphthoyl.
The term xe2x80x9caryloxy,xe2x80x9d as used herein, means an oxygen atom having an aryl substituent (e.g., xe2x80x94O-aryl).
The term xe2x80x9cester,xe2x80x9d as used herein, means compounds containing a substituted carboxylic acid (e.g., xe2x80x94COO-aryl).
The term xe2x80x9cacylxe2x80x9d or xe2x80x9ccarbonyl,xe2x80x9d as used herein, means a carbon to oxygen double bond, (e.g., Rxe2x80x94C(xe2x95x90O)xe2x80x94), which can be a radical of a carboxylic acid having the formula alkyl-COxe2x80x94, aryl-COxe2x80x94, arylalkyl-COxe2x80x94, cycloalkyl-COxe2x80x94, alkylcycloalkyl-COxe2x80x94 or heteroaryl-COxe2x80x94. Representative acyl groups include acetyl, propionyl, butanoyl and benzoyl groups.
The term xe2x80x9cacyloxy,xe2x80x9d as used herein, means an oxygen atom having an acyl substituent (e.g., xe2x80x94O-acyl), for example, xe2x80x94Oxe2x80x94C(xe2x95x90O)-alkyl.
The term xe2x80x9cacylamino,xe2x80x9d as used herein, means an amino moiety having an acyl substituent (e.g., xe2x80x94NH-acyl), for example, an amide with the formula xe2x80x94NHxe2x80x94(Cxe2x95x90O)-alkyl, a urea with the formula xe2x80x94NHxe2x80x94(Cxe2x95x90O)xe2x80x94NH-alkyl or a carbamate with the formula xe2x80x94NHxe2x80x94(Cxe2x95x90O)xe2x80x94OR, where R is an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, arylalkyl or heterocycloalkyl group.
The term xe2x80x9chalo,xe2x80x9d xe2x80x9chalogenxe2x80x9d or xe2x80x9chalide,xe2x80x9d as used herein, means a chloro, bromo, fluoro or iodo atom radical. Chlorides, bromides and fluorides are preferred halides.
The term xe2x80x9clower hydrocarbonxe2x80x9d (e.g., xe2x80x9clower alkylxe2x80x9d), as used herein, means a hydrocarbon chain comprised of from, unless otherwise stated, one to eight carbon atoms, preferably, one to six carbon atoms, and most preferably, one to four carbon atoms.
The term xe2x80x9cpolyhalo,xe2x80x9d as used herein, represents substitution of at least two halo atoms to a group modified by the term xe2x80x9cpolyhalo.xe2x80x9d
The term xe2x80x9caminosulfonyl,xe2x80x9d as used herein, represents a group having the formula: xe2x80x94SO2NR79R89, where R79 and R89 are, independently of one another, each a hydrogen atom or a lower alkyl (e.g., from 1 to 6 carbon atoms) or aryl group.
The term xe2x80x9csulfonyl,xe2x80x9d as used herein, represents a group having the formula: xe2x80x94S(O)2xe2x80x94.
When a variable appears more than once in a structural formula, for example, R59 for where X is xe2x80x94C(OR59)2xe2x80x94, the identity of each variable appearing more than once may be independently selected from the definition for that variable.
The term xe2x80x9cprodrug,xe2x80x9d as used herein, represents a compound that is a drug precursor, which following administration to a patient, releases a drug in vivo via some kind of chemical and/or physiological process (e.g., a prodrug on being brought to a physiological pH and/or through an enzyme action is converted to a desired drug form).
The term xe2x80x9ccompound of the formula (I.1) or (II.1)xe2x80x9d, as used herein, represents a compound having a chemical structure encompassed by the formula (I.1) or (II.1), and includes any and all enantiomers, stereoisomers, rotomers, tautomers and prodrugs of the compound. Compounds of the formula (I.1) or (II.1) also include their corresponding pharmaceutically-acceptable salts, solvates, esters and derivatives.
The term xe2x80x9cpharmaceutically-acceptable excipients,xe2x80x9d as used herein, includes any physiologically inert, pharmacologically inactive material known to one skilled in the art, which is compatible with the physical and chemical characteristics of the particular active ingredient selected for use. Pharmaceutically-acceptable excipients include polymers, resins, plasticizers, fillers, binders, lubricants, glidants, disintegrates, solvents, co-solvents, buffer systems, surfactants, preservatives, sweetening agents, flavoring agents, pharmaceutical grade dyes or pigments, and viscosity agents.
The term xe2x80x9cpharmaceutical composition,xe2x80x9d as used herein, means a combination of at least one inventive compound (e.g., PDE V inhibitor) and at least one pharmaceutically-acceptable excipient.
The terms xe2x80x9ccompound [having the formula (I)] or a pharmaceutical composition thereofxe2x80x9d include neutral, acidic and alkaline forms of the compound or composition, as well as solvates, esters and salts (as are defined below) thereof, and further includes derivatives of the inventive compounds.
The term xe2x80x9cpharmaceutically-acceptable salt,xe2x80x9d as used herein, means a cationic salt formed at an acidic (e.g., carboxyl) group or an anionic salt formed at a basic (e.g., amino) group of the compound. Many such salts are known in the art, for example, those that are described in WO 87/05297 (1987), which is hereby incorporated in its entirety by reference herein. Preferred cationic salts include the alkali-metal salts (e.g., sodium and potassium) and alkaline earth metal salts (e.g., magnesium and calcium). Preferred anionic salts include the halide (e.g., chloride), acetate and phosphate salts.
The phrase xe2x80x9ceffective amount,xe2x80x9d as used herein, means an amount of a compound or composition which is sufficient to significantly and positively modify the symptoms and/or conditions to be treated (e.g., provide a positive clinical response). The phrase xe2x80x9csafe and effective amount,xe2x80x9d as used herein, means that an xe2x80x9ceffective amountxe2x80x9d must also be safe, that is, an amount that is sufficient to provoke a positive response, yet is small enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment. The effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient being employed, the particular pharmaceutically-acceptable excipients utilized and like factors within the knowledge and expertise of the attending physician.
The phrase xe2x80x9cadministering [to a patient a safe and effective amount of the inventive compound],xe2x80x9d as used herein, refers to any mode of introducing any form (e.g., solid, liquid or gas) of the inventive compounds in vivo to a patient (e.g., human or mammal). For example, introduction of the inventive compound to a patient may be accomplished via oral ingestion (e.g., tablets, capsules, gels, solutions, etc.), adsorption, absorption (e.g., transmucosal sublingual or buccal administration), transdermal applications (e.g., topical applications via patches, lotions, etc.), suppositories, etc.
The term xe2x80x9coral dosage form,xe2x80x9d as used herein, means any pharmaceutical composition intended to be systemically administered to an individual by delivering the composition to the gastrointestinal tract of an individual, via the mouth of the individual. For purposes of the invention, the delivered form can be a tablet (coated or non-coated), solution, suspension or capsule (coated or non-coated).
The term xe2x80x9cinjection,xe2x80x9d as used herein, means any pharmaceutical composition intended to be systemically administered to a human or other mammal, via delivery of a solution or emulsion containing the active ingredient, by puncturing the skin of said individual, in order to deliver the solution or emulsion to the circulatory system of the individual either by intravenous, intramuscular, intraperitoneal or subcutaneous injection.
Other than as shown in the operating examples or where is otherwise indicated, all numbers used in the specification and claims expressing quantities of ingredients, reaction conditions, and so forth, are understood as being modified in all instances by the term xe2x80x9cabout.xe2x80x9d
The invention comprises a compound having the formula (I): 
where,
(a) R1 and R2 are, independently of one another, each a C1-15 alkyl group, branched or straight chain, with or without one or more substituents, such as a hydroxy or alkoxy substituent group, a C2-15 alkenyl group, branched or straight chain, with or without one or more substituents, a C2-15 alkynyl group, branched or straight chain, with or without one or more substituents, a C3-15 cycloalkyl group, with or without one or more substituents, an arylalkyl group, with or without one or more substituents, an aryl group, with or without one or more substituents, a heteroaryl group, with or without one or more substituents, xe2x80x94OR5, xe2x80x94COOR5, xe2x80x94C(O)R5 or xe2x80x94C(O)N(R5)2, where R5 is a hydrogen atom or a hydrocarbon radical, with or without one or more substituents, preferably, R5 is a hydrogen atom or an alkyl group, branched or straight chain, with or without one or more substituents; or
one of R1 and R2 is equal to a hydrogen atom, and the other one of R1 and R2 is defined the same as above;
(b) R3 is an aryl group, with or without one or more substituents, such as a hydroxy or alkoxy substituent group, a heteroaryl group, with or without one or more substituents, or a heterocyclic group having from 1 to 3 heteroatoms fused to a 5-or 6-membered aryl ring, with or without one or more substituents, with the proviso that R3 is not an aryl group substituted at its para position with a xe2x80x94Y-aryl group, where Y is a carbonxe2x80x94carbon single bond, xe2x80x94COxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(R21)xe2x80x94, xe2x80x94CON(R22)xe2x80x94, xe2x80x94N(R22)COxe2x80x94, xe2x80x94OCH2xe2x80x94, xe2x80x94CH2Oxe2x80x94, xe2x80x94SCH2xe2x80x94, xe2x80x94CH2Sxe2x80x94, xe2x80x94NHC(R23)(R24)xe2x80x94, xe2x80x94NR23SO2xe2x80x94, xe2x80x94SO2NR23xe2x80x94, xe2x80x94C(R23)(R24)NHxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CFxe2x95x90CFxe2x80x94, xe2x80x94CHxe2x95x90CFxe2x80x94, xe2x80x94CFxe2x95x90CHxe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CF2CF2xe2x80x94, 
where,
R21 is a hydrogen atom or a xe2x80x94CO(C1-4 alkyl), C1-6 alkyl, allyl, C3-6 cycloalkyl, phenyl or benzyl group;
R22 is a hydrogen atom or a C1-6 alkyl group;
R23 is a hydrogen atom or a C1-5 alkyl, aryl or xe2x80x94CH2-aryl group;
R24 is a hydrogen atom or a C1-4 alkyl group;
R25 is a hydrogen atom or a C1-8 alkyl, C1-8 perfluoroalkyl, C3-6 cycloalkyl, phenyl or benzyl group;
R26 is a hydrogen atom or a C1-6 alkyl, C3-6 cycloalkyl, phenyl or benzyl group;
R27 is xe2x80x94NR23R24, xe2x80x94OR24, xe2x80x94NHCONH2, xe2x80x94NHCSNH2, 
and
R28 and R29 are, independently of one another, each a C1-4 alkyl group or, taken together, a xe2x80x94(CH2)qxe2x80x94 group, where q is 2 or 3;
Wherein, R21 through R29 are with or without one or more substituents; and
(c) R4 is a C3-15 cycloalkyl group, with or without substituents, such as a hydroxy substituent group, a C3-15 cycloalkenyl group, with or without one or more substituents, or a heterocycloalkyl group of 3 to 15 members, with or without one or more substituents;
wherein, the optional one or more substituents for all the groups are chemically-compatible and are, independently of one another, each defined the same as recited above in the definition section.
The invention comprises at least one compound of the formula (I), which includes any and all enantiomers, stereoisomers, rotomers, tautomers and prodrugs of the at least one inventive compound. Compounds of the formula (I) also include their corresponding salts, solvates (e.g., hydrates), esters, and the like. The invention further comprises pharmaceutically-acceptable compositions prepared from an inventive compound or a mixture of inventive compounds, or a salt, solvate or ester thereof. The compounds of formula (I) can be useful for treating a variety of diseases, symptoms and physiological disorders, such as sexual dysfunction, especially impotence (e.g., erectile dysfunction).
A further understanding of the invention will be had from the following description of preferred embodiments.